新型内源性一氧化氮释放剂FK409的抗心绞痛作用

Antianginal effects of FK409, a new spontaneous NO releaser.

作者信息

Kita Y, Ozaki R, Sakai S, Sugimoto T, Hirasawa Y, Ohtsuka M, Senoh H, Yoshida K, Maeda K

机构信息

Department of Pharmacology, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.

出版信息

Br J Pharmacol. 1994 Dec;113(4):1137-40. doi: 10.1111/j.1476-5381.1994.tb17115.x.

DOI:10.1111/j.1476-5381.1994.tb17115.x

PMID:7889266

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1510548/

Abstract

The aim of this study was to compare antianginal effects of (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (FK409), a new spontaneous nitric oxide releaser, with those of isosorbide dinitrate (ISDN). We used two types of rat angina model; methacholine- and arginine vasopressin (AVP)-induced coronary vasospasm models. 2. In the in vitro study, FK409 showed 80 times more potent vasorelaxant effect in dog isolated coronary artery than ISDN (EC50 = 16.7 +/- 4.8 and 1340 +/- 320 nM, respectively). 3. In the rat methacholine-induced coronary vasospasm model, FK409 suppressed the elevation of ST segment dose-dependently and significantly at 0.1 mg kg-1, i.d. On the other hand, ISDN suppressed it significantly at 3.2 mg kg-1, i.d. In addition, the efficacy of 3.2 mg kg-1 ISDN in the model was almost the same as that of 0.1 mg kg-1 FK409. 4. In the above experiments, FK409 and ISDN decreased mean blood pressure significantly at the maximum dose tested (1.0 mg kg-1, i.d. and 3.2 mg kg-1, i.d., respectively) but did not change heart rate at these doses. Therefore, the hypotensive effect of FK409 was 10 times weaker than the antianginal effect of the compound, while those of ISDN were almost the same. 5. In the rat AVP-induced coronary vasospasm model, 32 mg kg-1 FK409 significantly inhibited the depression of ST segment 60 min after oral administration. On the other hand, 32 mg kg-1 ISDN did not inhibit it at 60 and 120 min after oral administration. 6. In conclusion, FK409 inhibits coronary vasospasm more potently in two types of rat angina models than ISDN. In addition, FK409 shows an antianginal effect more selectively that a hypotensive effect,compared with ISDN.

摘要

本研究旨在比较新型内源性一氧化氮释放剂（±）-（E）-乙基-2-[(E)-羟基亚氨基]-5-硝基-3-己烯酰胺（FK409）与硝酸异山梨酯（ISDN）的抗心绞痛作用。我们使用了两种大鼠心绞痛模型：乙酰甲胆碱和精氨酸加压素（AVP）诱导的冠状动脉痉挛模型。2. 在体外研究中，FK409在犬离体冠状动脉中的血管舒张作用比ISDN强80倍（EC50分别为16.7±4.8和1340±320 nM）。3. 在大鼠乙酰甲胆碱诱导的冠状动脉痉挛模型中，FK409在0.1 mg kg-1皮下注射时剂量依赖性且显著地抑制ST段抬高。另一方面，ISDN在3.2 mg kg-1皮下注射时显著抑制ST段抬高。此外，3.2 mg kg-1的ISDN在该模型中的疗效与0.1 mg kg-1的FK409几乎相同。4. 在上述实验中，FK409和ISDN在最大测试剂量（分别为1.0 mg kg-1皮下注射和3.2 mg kg-1皮下注射）时均显著降低平均血压，但在这些剂量下心率未改变。因此，FK409的降压作用比该化合物的抗心绞痛作用弱10倍，而ISDN的降压作用与抗心绞痛作用几乎相同。5. 在大鼠AVP诱导的冠状动脉痉挛模型中，32 mg kg-1 FK409口服给药60分钟后显著抑制ST段压低。另一方面，32 mg kg-1 ISDN在口服给药60分钟和120分钟后均未抑制ST段压低。6. 总之，在两种大鼠心绞痛模型中，FK409比ISDN更有效地抑制冠状动脉痉挛。此外，与ISDN相比，FK409的抗心绞痛作用更具选择性，降压作用较弱。